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Neurology - Neuro - Degenerative Diseases (AD, PD, HD) (*Neurodegenerative…
Neurology - Neuro - Degenerative Diseases (AD, PD, HD)
*Neurodegenerative Diseases
*Alzheimer's Disease
Mnemonic for Proteins:
think of the 2 days of the year you get drunk, forget everything and get lost, and the
DRINKING AGES (19,21)
--> New Years = 1st, Lewy's Birthday = Jan 14,
--> PSEN2 = presenilin 2 = chromosome 1
--> PSEN1 = presenilin 1 = chromosome 14
DRINKING AGES (19,21) in Windsor and Detroit when you get WASTED and FORGET
--> ApoE2 = chromosome 19
--> AppoE4 = chromosome 19
-->
APP protein
= amyloid precursor protein
= chromosome 21
Early onset vs Late Onset AD
early onset (age < 65) =
familial
AD
--> APP
--> PSEN2 = presenilin 2 = chromosome 1
--> PSEN1 = presenilin 1 = chromosome 14
late onset (age < 65) =
sporadic
AD form
--> AppoE4 = increases sporadic
--> AppoE2 = decreases sporadic
AD - Epidemiology
5-10% is genetic
usually die within 3-10 years
50% of people over 85 get AD.
Down's Syndrome = Trisomy 21
--> very high risk for AD since they have extra APP genes on chromosome 21
--> more APP produced and risk for beta amyloid plaques
can't technically diagnose without brain biopsy after death
--> must rule out other causes of dimentia first
AD - Pathophys
AD = Alzheimer's Disease = Autosomal Dominant
tau and amyloid proteins accumulate in the brain
TAU NFTs = inside cells
neurofibrillary tau complex = neurofibrillary tangle NFT
tau is a microtubule-binding protein
--> think of TAU as railroad ties on the railroads of microtubules used for transport
--> in AD tau gets hyperphosphorylted and forces microtubules to dissassemble and leave behind tau neurofibrillary tangles
--> look like a cone of fibres
--> remember "if drunk=dimentia you get tangled up in tau neurofibrillary tangles"
BETA AMYLOID PLAQUES = outside cells and on blood vessels (amyloid angiopathy)
can lead to CAA = cerebral amyloid angiopathy
--> recall one of the risk factor As for Hemmoragic Stroke
amyloid plaques stain in positive in silver
Beta amyloid specifically is the insoluble form of the chopped up APP --> not soluble so accumulates in cells
Histology
beta amyloid plaques
neurofibrillary tangles
APC and BETA AMYLOID PLAQUES in AD
APC = amyloid precursor protein
is cleaved into amyloid
beta amyloid plaques are accumulation of the protein in the brain and blood vessel walls
APC gene is found on Chromosome 21
--> Trisomy 21 has an extra copy of chromosome 21
--> Downs usually get APC mutated AD by age 50
APC gene on Chromosome 21 - Down syndrome
AMYLOID SUBTYPES
FBD = familial British dimentia --> chromosome 13
Icelandic --> Hchwa-1
Hereditary Leptomeningeal and vitreous microvascular amyloid --> affecting multiple
organs
transthyretin related amyloid --> think trans = poly = familial amyloid polyneuropathy type 1
Finnish familial amyloidosis - Gelsolin
--> think all Americans are jealous of the Finnish people = Gelsolin amyloid
Mutated PROTEINS (other than tau and amyloid)
APP = amyloid precursor protein
--> on chromosome 21
--> remember large cause is amyloid plaques in the brain
presenilin 1,2 = gamma secretase enzyme --> cut the APP so mutation makes the amyloid insoluble and accumulate
Apo E2 --> DECREASES risk of sporadic form (5% of cases; 40s,50s age)
Apo E4 --> INCREASES risk of sporadic form (95% of cases; 65+ age)
--> think Apo4 is FOUR the MORE SPORadic FORM
--> note the Apo protein is supposed to breakdown beta amyloid -->> so mutation makes it less good at this
*Parkinson's Disease
Treatment of PD
LEVOdopa/carbidopa = 1st line for advanced PD
Preventing levoDOPA breakdown
DDIs, COMT inhibitors, and MAO inhibitors
1 more item...
*Levodopa/Carbidopa PD treatment
behaviour changes and agitation
--> high dopamine in brain can cause this
--> the worst side effect of LDOPA
--> made worse with carbidopa since it only increases the CNS dopamine even higher
Levodopa can cross the Blood BB where dopamine cannot
overtime levoDOPA starts to have high
fluctating ON/OFF periods
--> ON = good movement
--> OFF = akinesia / bradykinesia
Levodopa fluctating ON/OFF periods
overtime levoDOPA starts to have high
fluctating ON/OFF periods
--> ON = good movement
--> OFF = akinesia / bradykinesia
this is nothing to to do with the medication or its metabolism
--> eventually these ON/OFF periods become independent of the dosing
cause of ON/OFF periods is slow and progressive degeneration of the Substantia nigra and lower Dopamine levels
1 more item...
PD Ubiquitin/Protease Protein Degredation Cycle - Mutated genes
autosomal recessive
they all make up the protease complex needed for the Ubiquitin/Protease Protein Degredation Cycle
"U BE QUITIN going to see DJ PIINK at the PARK"
--> parkin genes = PARK2, PARK7,
--> PINK1 gene
--> DJ gene
--> ALL make the ubiquitin protease complex for degrading proteins
--> make the
Autosomal Dominant
LRRK2, SNCA genes
Predisposing genes
UCHL1, GBA gene
NOTES
think of the 2 major CNS degenerative diseases have hallmarks of either alpha or beta collection of proteins in the CNS
PD --> alpha synuclein deposits or lesions
--> called Lewy bodies (when in the soma of neuron)
--> Lewy neurites (when in other parts of neurons, usually axons)
AD --> beta amyloid plaques or lesions
*substantia Nigra
in the midbrain at the level of the colliculi
Clinical Progression of PD
BRAAK 1/2 - first 5 years
--> no symptoms
-->Lewy bodies start
BRAAK 3/4 - 5-10 years
--> classic TRAPS symptoms
BRAAK 5/6 - 10+ years
--> dementia
Diagnosis
--> requires ALL these
PET scan
MRI scan
DOPA challenge (response to L-DOPA)
--> other tests: smell test +/-
--> SPECT test
Epidemiology
increased risk of dimentia in late stages
Pathophys
Dopamine - Acetylcholine imbalance
NOT just dopamine affected
better to think of as imbalanace of less dopamine and too much ACh
reason why ACh anti-muscarinics are used to treat tremor of PD
Lewy Bodies and Lewy Neurites
composed of alpha-synuclein protein buildup
Lewy Body = inside the cell
Lewy neurite = outside the soma cell body--> usually in the axons
Dopamine
loss of dopamine producing
pars compacta of substantia nigra
of the midbrain
reduction in
nigrostriatal dopaminergic pathway
Clinical Symptoms PD
Other Outcomes of PD
70% get REM sleep disorder
--> major problem is sleep disorder for PD
--> poor sleep at night and sleep a lot during the day
--> think of grandpa always napping during the day and up all night
--> treat daytime sleepiness with modafinil
40% of PD get depression and anxiety
15-40% get dementia
olfactory = smell dysfunction common
"Parkinson's Disease
TRAPS
your body"
- T = tremor
--> pill rolling tremor
- R = rigidity
--> cogwheel + lead pipe in arms usually
- A = akinesia/bradykinesia
- P = postural instability
- S = shuffling gate
--> this increases to postural instability (late stage PD)
*ALS = Amyotrophic Lateral Sclerosis
= Lou Gehrig's Disease
Epidemiology
die within 5 years --> usually respiratory failure
PathoPhys
can effect both UMNs and LMNs, including corticobulbar tracts in early onset
note ALL 3 major types are PROGRESSIVE
--> they start off slow and slowly progress and get worse
hyperphosphorylated tau (round lobar pick bodies) --> ubiquitinated TDP43 protein
ubiquitinated TDP43 protein accumulation in the anterior horns of spinal cord = LMN
--> breakdown of soma bodies in the anterior horn
--> get grouped muscle atrophy since these cells each innervate multiple muscles
Mutated Proteins/Genes
remember Lou Gehrig was THE DARNEST PLAYER = TDP43 AND GENUINE = angiogenin SUPERMAN ON SOD
THE DARNEST PLAYER = TDP43
AND GENUINE = angiogenin
SUPERMAN ON SOD = superoxide dismutase
ubiquitinated TDP43 protein
--> form hyperphosphorylated tau (round lobar pick bodies)
SMN1 = spinal motor neuron type 1 gene
--> gene that Stephen Hawking has mutated
3 Major Types
note need clinical evidence of
both UMN and LMN disease
Progressive Bulbar Palsy
more early onset of the disease for many
dysarthria = trouble speaking
--> scanning speech (scan for syllables, slurring)
dysphasia = trouble swallowing
Progressive LMN Muscular Atrophy
LMN control lost, upper cortex and tracts intact
Progressive UMN Lateral Sclerosis
pathology ONLY in the motor cortex and corticospinal tracts
*Prion Disorders = transmissible spongiform
encephalopathies TSEs
3 Key Histological Markers:
spongiform vaculoar change
astrocyte proliferation = form of gliosis
neuronal shrinkage
Pathophys
progressive ataxia = lose balance at first
very rapid dimentia onset = weeks to months
Subtypes
:
Sporadic Creutzfeldt-Jakob disease (CJD)
Variant CJD (BSE = Bovine Spongiosum Ecephalopathy in humans)
*Dementia
1st cause = Alzhiemers
2nd cause = Vascular dementia
--> multiple small infarcts to the brain over time
--> stepwise decline = sharp decline at infarcts / no decline in between
Causes of Dementia Differentials
in dementia their brains have
VANISHED
...
V
= Vascular and Vitamins B1,3,12
A
= Alzheimer's (exclusion)
N
= NPH = normal pressure hydrocephalus
I
= Infections (UTI / Jacob-Creuz / syphilis)
S
= sustance abuse (alcohol, etc.)
H
= hypothyroidism (TFTs)
E
= electrolyte imbalance (hyponatremia, hypokalemia)
D
= depression
Dementia vs. Delerium
for dementia, see other notes
Clinical Cases
1 more item...
Causes of Delerium
Delerium is ALWAYS caused by an underlying condition
--> most common iinn elderly is UTI
Delerium is thus reversible
--> treat the underlying cause
1 more item...
Treatment of Delerium
Delerium is ALWAYS caused by an underlying condition
--> most common iinn elderly is UTI
Delerium is thus reversible
--> treat the underlying cause
--> use high-potency antipsychotic = haloperidol
--> 2nd gen antipsych = quetiopine
"Delerium UTI =
QUIET down for HALO PERIOD
time = Angels"
QUIET
= quetiopine
HALO PERIOD
= haloperidol
1 more item...
*FTLD =
Frontotemporal Lobar Degeneration/Dementia
Epidemiology
2nd most common genetic form of early onset (< 65 age)
25-50% FTLD genetic
usually live for about 20 years
Mutated Proteins
tau protein
ubiquitinated TDP-43 protein
FUS --> only disease starts with an F
Pathophys
hyperphosphorylated tau "round pick bodies"
--> think the round pick bodies are like "lobar
grapes" = Frontotemporal LOBAR
spongiosis = intracellular adema
in MRI can clearly see the sulci are larger in the frontal and temporal lobes
Symptoms
Parkinsonian symptoms
UMN/LMN symptoms like in ALS
key marker = reduced speech at first --> social isolation
second mute and bedbound
Treatments
Clinical Cases
Clinical Case
Notes
:
note that
Clinical Case
Increase Ach
ACh Esterase inhibitors
donepazil
--> think of dementia lady cooking terrible food with oven left open...
-->
DONE a PETITIE (BRAZil fruit cake)
*Lewy body Dementia
Epidemiology
note that MSA = multiple system atrophy is a different form of Lewy body accumulation and degeneration, but with more motor functions
Abnormal Proteins
alpha-synuclein (Lewy bodies)
Pathophys
"ha -
LEWY
- cinnations"
--> intracellular Lewy bodies cause hallucinations and Parkinsonian symptoms
Symptoms
Dimentia is NOT a disease --> it is a set of symptoms
--> loss of memory and learning
hallucinations and Parkinsonian symptoms
"ha -
LEWY
- cinnations"
--> fast onset of dimentia and frequent hallucinations
--> think of Lewy hallucinating
*Huntington's Disease
= polyglutamine disease (CAG)
CAG repeats
"CA - G"
= Gain of function --> lose Acetylation
Pathophys of HD
CAG repeats --> cause deacetylation --> trasncription silencing
Pathophys
Microscope
ubiquitin and huntingin deposits --> lead to neuronal loss
gliosis in basal ganglia (proliferation of certain glial cells and fibres = mainly astrocytes)
Caudate and Putamen Atrophy
remember: "
CAG
=
C
audate loses
A
Ch and
G
ABA" --> also increased dopamine levels
Caudate atrophy --> causes Chorea = main symptom
the atrophy of the caudate allows the ventricles to expand in their place -->
hydrocephalous ex vacuo
CAG Repeats
autosomal dominant trinucleotide (CAG) repeat disorder on HUntington gene (HTT) chromosome 4
--> remember: "You HUNT with an AUTO D 34"
--> 34 = 3 triplet CAG on chromosome 4
note CAG = glutamine
Signs and Symptoms
chorea
Epidemiology
Almost always younger or middle-aged men or women
Anticipation = earlier onset with each generation = more CAG repeats get passed on each generation
average onset = age 40
die within 10-20 years
NOTES
think of the 2 major CNS degenerative diseases have hallmarks of either alpha or beta collection of proteins in the CNS
PD --> alpha synuclein deposits or lesions
--> called Lewy bodies (when in the soma of neuron)
--> Lewy neurites (when in other parts of neurons, usually axons)
AD --> beta amyloid plaques or lesions
